IL-37 Is a Novel Proangiogenic Factor of Developmental and Pathological Angiogenesis

Arterioscler Thromb Vasc Biol. 2015 Dec;35(12):2638-46. doi: 10.1161/ATVBAHA.115.306543. Epub 2015 Oct 29.

Abstract

Objective: Angiogenesis is tightly controlled by growth factors and cytokines in pathophysiological settings. Interleukin 37 (IL-37) is a newly identified cytokine of the IL-1 family, some members of which are important in inflammation and angiogenesis. However, the function of IL-37 in angiogenesis remains unknown. We aimed to explore the regulatory role of IL-37 in pathological and physiological angiogenesis.

Approach and results: We found that IL-37 was expressed and secreted in endothelial cells and upregulated under hypoxic conditions. IL-37 enhanced endothelial cell proliferation, capillary formation, migration, and vessel sprouting from aortic rings with potency comparable with that of vascular endothelial growth factor. IL-37 activates survival signals including extracellular signal-regulated kinase 1/2 and AKT in endothelial cells. IL-37 promoted vessel growth in implanted Matrigel plug in vivo in a dose-dependent manner with potency comparable with that of basic fibroblast growth factor. In the mouse model of retinal vascular development, neonatal mice administrated with IL-37 displayed increased neovascularization. We demonstrated further that IL-37 promoted pathological angiogenesis in the mouse model of oxygen-induced retinopathy.

Conclusions: Our findings suggest that IL-37 is a novel and potent proangiogenic cytokine with essential role in pathophy siological settings.

Keywords: cytokines; endothelial cell; inflammation; interleukins; oxygen-induced retinopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology*
  • Animals
  • Animals, Newborn
  • Cell Hypoxia
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Interleukin-1 / metabolism
  • Interleukin-1 / pharmacology*
  • Interleukin-1 / toxicity
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / drug effects*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Retinal Neovascularization / chemically induced*
  • Retinal Neovascularization / metabolism
  • Retinal Neovascularization / pathology
  • Retinopathy of Prematurity / chemically induced*
  • Retinopathy of Prematurity / metabolism
  • Retinopathy of Prematurity / pathology
  • Time Factors
  • Transfection

Substances

  • Angiogenesis Inducing Agents
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • IL37 protein, human
  • Interleukin-1
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases